CN102351963A - Preparation method of galactosylated fatty acylchitosan - Google Patents
Preparation method of galactosylated fatty acylchitosan Download PDFInfo
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- CN102351963A CN102351963A CN2011103275727A CN201110327572A CN102351963A CN 102351963 A CN102351963 A CN 102351963A CN 2011103275727 A CN2011103275727 A CN 2011103275727A CN 201110327572 A CN201110327572 A CN 201110327572A CN 102351963 A CN102351963 A CN 102351963A
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Abstract
The invention discloses a preparation method of galactosylated fatty acylchitosan, which comprises the following steps: by using chitosan as a raw material and alkyl sulfonic acid as a reaction medium and amino-group protective agent, reacting acyl chloride with chitosan; after the reaction finishes, filtering, refluxing the organic solvent to remove alkyl sulfonic acid, carrying out vacuum filtration, and drying to obtain acylated chitosan; and reacting the acylated chitosan with lactobionic acid, carrying out vacuum filtration, removing impurities from the filter residues, and drying to obtain the galactosylated fatty acylchitosan. The method has the advantages of mild preparation conditions, short reaction time and complete and thorough reaction, and is simple to operate; and the alkyl sulfonic acid and the 2- amino group of the chitosan are combined into a salt to protect the amino group so as to leave a site for the insertion of the galactosyl group, thereby obtaining the galactosylated fatty acylchitosan carrier material.
Description
Technical field
The present invention relates to the medication preparation field, be specifically related to a kind of preparation method of active targeted chitosan micella solid support material.
Background technology
Chitosan (chitosan) is the product of chitin N-deacetylation gained; It is a kind of natural polymer materials; Have wide material sources, cheap, good biocompatibility, non-immunogenicity, good adsorption property and environment friendliness property and advantage such as nonpoisonous and tasteless; Be widely used in agricultural, makeup, food and pharmaceutical industries, be called as one of polymer latex beam material of tool potentiality of 21 century.Chitosan with compact crystalline structure is insoluble in many organic solvents; Limited its application as the smart polymeric material; Research to chitosan at present mainly concentrates on its modification aspect, in its molecule, introduces different groups and improves solvability or make it to have new function.In numerous modifications, the research of introducing fatty acyl group is more, has both solved poorly soluble problem, gives simultaneously that it is amphipathic, has enlarged the purposes of chitosan in each field.Also has carboxylated, etherificate, alkylation, esterification, hydroxylation, chelating, oxidation, grafting and the research such as crosslinked of chitosan in addition.
Yet, among the preparation method of present various fatty acyl chitosans, exist reagent toxicity big, complex process or reaction conditions be problem such as harshness comparatively, has limited the realization that its widespread production is utilized.King Zhou Yuyong acetic acid and acetone are solvent, with chitosan and anhydride reaction, obtain the maleylation chitosan, but hydroxyl also has part to be replaced by acid anhydrides, fails to realize complete orienting response.Huang Liyao is a reaction medium with chloroform, pyridine, prepares the long aliphatic chain acylation chitosan of complete hydrophobization, but complex pretreatment, overlong time.Liang Sheng is a medium with the glycine hydrochloride ionic liquid, preparation succinyl chitosan, but glycine hydrochloride is ion liquid synthetic comparatively loaded down with trivial details, and reactions step is more.Sum up the synthesis method of present acylation chitosan, all unsatisfactory, hindered the exploitation and the application of chitosan.
Effective target spot of the asialoglycoprotein receptor Chang Zuowei liver target on hepatic parenchymal cells surface and receive extensive concern.Because semi-lactosi can be by the asialoglycoprotein receptor specific recognition, therefore often with itself and the pharmaceutical carrier of macromole coupling, the targeted delivery of realization medicine as the liver specificity target.With the alkylsulphonic acid is medium, makes the reaction of chitosan and fat acyl chloride obtain the fatty acyl chitosan, and inserting galactosyl has the amphipathic carrier of target property with preparation research does not again have report as yet.Amphipathic carrier with target property not only can increase the solubleness of hydrophobic drug greatly, can also make the drug targeting privileged site, improves the selectivity of medicine greatly, and huge meaning is arranged in drug delivery system.
Summary of the invention
The objective of the invention is to according to above-mentioned deficiency of the prior art, a kind of preparation method of new glycosyl galactose fatty acyl chitosan is provided.
The present invention realizes above-mentioned purpose through following technical scheme:
A kind of preparation method of glycosyl galactose fatty acyl chitosan; Step is following: be raw material with the chitosan; With the alkylsulphonic acid is reaction medium and amino protecting agent; With acyl chlorides and chitosan reaction, reaction terminating after-filtration, organic solvent reflux and remove alkylsulphonic acid; Suction filtration, drying obtain acylation chitosan; Acylation chitosan and lactobionic acid reaction through suction filtration, filter residue removal of impurities, drying, obtain glycosyl galactose fatty acyl chitosan.
Preparing method's kind of above-mentioned glycosyl galactose fatty acyl chitosan, said chitosan molecule amount is 5000 ~ 150000, deacetylation is 85% ~ 95%.
Said alkylsulphonic acid is to combine salifiable acid with chitosan 2 bit aminos, is preferably methylsulfonic acid and (claims methanesulfonic again, methylsulphonic acid, molecular formula CH
4O
3S).
Said acyl chlorides is preferably carbon chain lengths at C
12~ C
16Fat acyl chloride, the best is hexadecanoyl chloride or lauroyl chloride.
Said chitosan and acyl chlorides mol ratio are preferably 1:3 ~ 1:19, and both can stir in reaction process and make reaction more complete, the preferred 15min of churning time.
Acyl chlorides among the above-mentioned preparation method and chitosan reaction, the acyl chlorides of different carbon chain lengths and the temperature of chitosan reaction have nothing in common with each other, and scope is between 10 ℃ ~ 20 ℃, and the reaction times is preferably 1h.
Said organic solvent refluxed and removes in the step of alkylsulphonic acid, and organic solvent is preferably acetone, 65 ℃ of condition refluxed 2 hours.
Among the above-mentioned preparation method, acylation chitosan has the backbone structure similar with the chitosan raw material, 3 in the molecule, and the 6-hydroxyl is partly or entirely replaced, and structure is suc as formula 1, and hydroxyl or amino group substitution degree scope are between 0.023 ~ 0.74.
Said acylation chitosan and lactobionic acid reaction; Preferably under the activation of 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), carry out with acylation chitosan; Acylation chitosan and EDCHCl can be dissolved in organic solvents such as dimethyl sulfoxide (DMSO) or chloroform; Be more conducive to the carrying out that react, preferred dimethyl sulfoxide (DMSO) (DMSO).
Compared with prior art, the present invention has following beneficial effect:
The chitosan raw material of the inventive method is a kind of wide material sources, no cytotoxicity, degradable, the natural polymeric material of good biocompatibility.This method preparation condition is gentle, simple to operate, the reaction times short; React completely simultaneously thoroughly, alkylsulphonic acid combines salify with chitosan 2 bit aminos, and protection is amino; For the access of semi-lactosi group stays the site, thereby obtain glycosyl galactose fatty acyl chitin carrier material.
Description of drawings
Fig. 1 is that molecular weight is 30000 the chitosan raw material and the infared spectrum of glycosyl galactose hexadecanoyl chitosan thereof.Wherein a represents chitosan raw material INFRARED SPECTRUM, and b represents the INFRARED SPECTRUM of glycosyl galactose hexadecanoyl chitosan.
Fig. 2 is that molecular weight is 150000 the chitosan raw material and the 1H-NMR collection of illustrative plates of glycosyl galactose hexadecanoyl chitosan thereof.Wherein c represents the 1H-NMR collection of illustrative plates of chitosan raw material, and d represents the 1H-NMR collection of illustrative plates of glycosyl galactose hexadecanoyl chitosan.
Fig. 3 is that molecular weight is 150000 the chitosan raw material and the infared spectrum of glycosyl galactose dodecanoyl chitosan thereof.Wherein e represents chitosan raw material INFRARED SPECTRUM, and f represents the INFRARED SPECTRUM of glycosyl galactose dodecanoyl chitosan.
Embodiment
Further explain the present invention below in conjunction with specific embodiment, but embodiment does not do any type of qualification to the present invention.In following examples, except that specified otherwise, be concentration expressed in percentage by volume in the reagent of percentage concentration.
The preparation of embodiment 1 glycosyl galactose hexadecanoyl chitosan
1. (M=30 000 to get chitosan; Deacetylation 85%) 1.0 g are in three-necked bottle; Adding 30 ml methylsulfonic acids slowly is stirred to and is uniformly dispersed; Add hexadecanoyl chloride,, add 100ml distilled water and 25% ammoniacal liquor after reaction is accomplished with termination reaction in 20 ℃ (or 10 ℃, 15 ℃) reaction 1h; Filter; Reflux removing lipid acid with a large amount of acetone then, suction filtration is drying to obtain the raw molecule amount and is 30,000 hexadecanoyl chitosan.This hexadecanoyl chitosan of 0.4 g is placed 100 ml three-necked bottles; Adding 20 ml DMSO is uniformly dispersed; Again 0.8 g lactobionic acid and 0.8 g EDCHCl are dissolved in the solution adding among the 20 ml DMSO; In 30 ℃ of reaction 24h; Suction filtration; Removing unreacted lactobionic acid and EDCHCl, the suction filtration after drying promptly gets the raw molecule amount and is 30,000 glycosyl galactose hexadecanoyl chitosan to filter residue with a large amount of distilled water flushings.With the acylation reaction temperature is that 10 ℃, the 15 ℃ products that obtain are compared, and the solubility property of product in dimethyl sulfoxide (DMSO) that 20 ℃ of reactions obtain is more satisfactory; Then the mol ratio of under 20 ℃ of temperature of reaction, having investigated chitosan and hexadecanoyl chloride respectively is 1:3～1:13 products therefrom solubility property and productive rate, and wherein aspects such as the solubility property of 1:3～1:6 mol ratio products therefrom, productive rate are more excellent.The infared spectrum of chitosan raw material and glycosyl galactose hexadecanoyl chitosan thereof is seen Fig. 1.A is a chitosan raw material infared spectrum among Fig. 1, and b is the infared spectrum of glycosyl galactose hexadecanoyl chitosan, and glycosyl galactose palmitoylation chitosan is at 2920 cm
-1, 2850 cm
-1The vicinity is saturated C-H stretching vibration absorption peak, 1742 cm
-1The vicinity is the stretching vibration absorption peak of ester carbonyl group, 1378 cm
-1Represent the in-plane bending vibration of saturated C-H, 721 cm
-1The place is the correlation absorption band of long-chain methylene radical, proves that long acyl successfully grafts in the chitosan molecule.
2. (M=150 000 to get chitosan; Deacetylation 95%) 1.0 g; In three-necked bottle, add 30 ml methylsulfonic acids and slowly be stirred to and be uniformly dispersed, add hexadecanoyl chloride; In 20 ℃ (or 10 ℃, 15 ℃) reaction 1h; Add 100ml distilled water and 25% ammoniacal liquor after reaction is accomplished with termination reaction, filter, reflux to remove lipid acid with a large amount of acetone then; Suction filtration is drying to obtain the raw molecule amount and is 150,000 hexadecanoyl chitosan.This hexadecanoyl chitosan of 0.4 g is placed 100 ml three-necked bottles; Adding 20 ml DMSO is uniformly dispersed; Again 0.8 g lactobionic acid and 0.8 g EDCHCl are dissolved in the solution adding among the 20 ml DMSO; In 30 ℃ of reaction 24h; Suction filtration; Removing unreacted lactobionic acid and EDCHCl, the suction filtration after drying promptly gets the raw molecule amount and is 150,000 glycosyl galactose hexadecanoyl chitosan to filter residue with a large amount of distilled water flushings.20 ℃ of products that obtain with 10 ℃, 15 ℃ reactions of acylation reaction temperature are compared, and solubility property is more satisfactory, dissolves in organic solvents such as dimethyl sulfoxide (DMSO) and chloroform; Then the mol ratio of under 20 ℃ of temperature of reaction, having investigated chitosan and hexadecanoyl chloride respectively is 1:3～1:19 products therefrom solubility property and productive rate, and wherein aspects such as the solubility property of 1:3～1:6,1:17～1:19 molar ratio range products therefrom, productive rate are more excellent.Fatty acyl group substitution value scope is 0.023 ~ 0.74.Galactosyl substitution value scope is 0.301 ~ 0.54.
The 1H-NMR collection of illustrative plates of chitosan raw material and glycosyl galactose hexadecanoyl chitosan is seen Fig. 2, and c is a chitosan, and d is a glycosyl galactose hexadecanoyl chitosan.Compare with chitosan raw material (M=150 000, deacetylation 95%), the nuclear-magnetism H spectrum of glycosyl galactose hexadecanoyl chitosan new absorption peak occurs at δ=0.88 ppm, δ=1.42 ppm, δ=1.57 ppm places, the corresponding long acyl of difference-CH
3,-CH
2,-CH
2C=O.The proof long acyl successfully inserts in the chitosan.
The results of elemental analyses of 150,000 molecular weight glycosyl galactose hexadecanoyl chitosans: C, H, N element proportion are respectively 40.68%, 7.3%, 7.27% in the 150000 molecular weight chitosan raw molecules; C, H, N element proportion are respectively 66.1%, 10.27%, 3.5% in the hexadecanoyl chitosan; C, H, N element proportion are respectively 60.57%, 9.29%, 1.43% in the glycosyl galactose hexadecanoyl chitosan, can know that fatty acyl group and galactosyl all successfully insert in the chitosan molecule.
The preparation of embodiment 2 glycosyl galactose dodecanoyl chitosans
(M=150 000 to get chitosan; Deacetylation 95%) 1.0 g; In three-necked bottle, add 30 ml methylsulfonic acids and slowly be stirred to and be uniformly dispersed, add lauroyl chloride; In 15 ℃ (or 10 ℃) reaction 1h; Add 100ml distilled water and 25% ammoniacal liquor after reaction is accomplished with termination reaction, filter, reflux to remove lipid acid with a large amount of acetone then; Suction filtration is drying to obtain the raw molecule amount and is 150,000 dodecanoyl chitosan.This dodecanoyl chitosan of 0.4 g is placed 100 ml three-necked bottles; Adding 20 ml DMSO is uniformly dispersed; Again 0.8 g lactobionic acid and 0.8 g EDCHCl are dissolved in the solution adding among the 20 ml DMSO; In 30 ℃ of stirring reaction 24h; Suction filtration; Removing unreacted lactobionic acid and EDCHCl, the suction filtration after drying promptly gets the raw molecule amount and is 150,000 glycosyl galactose dodecanoyl chitosan to filter residue with a large amount of distilled water flushings.With 10 ℃ of reacting phase ratios, the product phased soln performance that 15 ℃ of reactions obtain is more satisfactory, can be dissolved in organic solvents such as dimethyl sulfoxide (DMSO) preferably; Then the mol ratio of under 15 ℃ of temperature of reaction, having investigated chitosan and lauroyl chloride respectively is 1:3～1:13 products therefrom solubility property and productive rate, and wherein aspects such as the solubility property of 1:3～1:6 mol ratio products therefrom, productive rate are better.The fatty acyl group substitution value is 0.172 ~ 0.356.
The infared spectrum of chitosan raw material and glycosyl galactose dodecanoyl chitosan is seen Fig. 3, and e is a chitosan raw material infared spectrum, and f is the infared spectrum of glycosyl galactose dodecanoyl chitosan.Compare with chitosan raw material (M=150 000, deacetylation 95%), glycosyl galactose dodecanoyl chitosan is at 2920 cm
-1, 2850 cm
-1The vicinity is saturated C-H stretching vibration absorption peak, 1742 cm
-1The vicinity is the stretching vibration absorption peak of ester carbonyl group, 1467 cm
-1, 1378 cm
-1Represent the in-plane bending vibration of saturated C-H, 721 cm
-1The place is the correlation absorption band of long-chain methylene radical, proves that long acyl successfully grafts in the chitosan molecule.
Claims (8)
1. the preparation method of a glycosyl galactose fatty acyl chitosan; It is characterized in that step is following: be raw material with the chitosan; With the alkylsulphonic acid is reaction medium and amino protecting agent; With acyl chlorides and chitosan reaction, reaction terminating after-filtration, organic solvent reflux and remove alkylsulphonic acid; Suction filtration, drying obtain acylation chitosan; Acylation chitosan and lactobionic acid reaction through suction filtration, filter residue removal of impurities, drying, obtain glycosyl galactose fatty acyl chitosan.
2. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that said chitosan molecule amount is 5000 ~ 150000, deacetylation is 85% ~ 95%.
3. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that said alkylsulphonic acid is a methylsulfonic acid.
4. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that said acyl chlorides is that carbon chain lengths is at C
12~ C
16Fat acyl chloride.
5. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that said chitosan and acyl chlorides mol ratio are 1:3 ~ 1:19.
6. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, the temperature that it is characterized in that acyl chlorides and chitosan reaction is 10 ℃ ~ 20 ℃, and the reaction times is 1h.
7. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that said organic solvent is an acetone.
8. according to the preparation method of the said glycosyl galactose fatty acyl of claim 1 chitosan, it is characterized in that the reaction of acylation chitosan and lactobionic acid is under the activation of 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, to react with acylation chitosan.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104688627A (en) * | 2015-03-20 | 2015-06-10 | 青岛华仁技术孵化器有限公司 | Acne eliminating mask |
| CN109503265A (en) * | 2018-12-17 | 2019-03-22 | 安徽省司尔特肥业股份有限公司 | A kind of preparation method of polylactic acid porous slow release-controlled film |
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| WO2006121059A1 (en) * | 2005-05-09 | 2006-11-16 | National University Corporation Nagoya University | Chitosan derivative and method for producing same |
| CN101074271A (en) * | 2006-05-19 | 2007-11-21 | 齐长有 | Production and use for amphipathic chitose derivative |
| CN101704907A (en) * | 2009-12-08 | 2010-05-12 | 广东药学院 | Method for preparing acylation chitosan |
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Patent Citations (3)
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| WO2006121059A1 (en) * | 2005-05-09 | 2006-11-16 | National University Corporation Nagoya University | Chitosan derivative and method for producing same |
| CN101074271A (en) * | 2006-05-19 | 2007-11-21 | 齐长有 | Production and use for amphipathic chitose derivative |
| CN101704907A (en) * | 2009-12-08 | 2010-05-12 | 广东药学院 | Method for preparing acylation chitosan |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104688627A (en) * | 2015-03-20 | 2015-06-10 | 青岛华仁技术孵化器有限公司 | Acne eliminating mask |
| CN109503265A (en) * | 2018-12-17 | 2019-03-22 | 安徽省司尔特肥业股份有限公司 | A kind of preparation method of polylactic acid porous slow release-controlled film |
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Application publication date: 20120215 |